E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. Objective: To compare progression-free survival (PFS) per RECIST 1.1 assessed by a blinded central imaging vendor. 2. Objective: To compare OS between pembrolizumab plus BSC versus placebo plus BSC.
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E.2.2 | Secondary objectives of the trial |
1. Objective: To compare objective response rate (ORR) per RECIST 1.1 assessed by a blinded central imaging vendor. 2. Objective: To evaluate the duration of response (DOR), disease control rate (DCR) and time to progression (TTP), per RECIST 1.1 assessed by a blinded central imaging vendor. 3. Objective: Evaluate the safety and tolerability profile of pembrolizumab.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
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E.3 | Principal inclusion criteria |
1. Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research (FBR). However, the subject may participate in the main trial without participating in FBR. 2. Be 18 years of age on day of signing informed consent. 3. Have a HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible). Radiologic confirmation diagnosis is provided by the study site. Definition of radiological confirmation: Clinical findings consistent with the diagnosis of liver cirrhosis and a liver mass measuring at least 2 cm with characteristic vascularization (intense enhancement seen in the hepatic arterial-dominant phase and contrast washout in the late portal venous phase) seen in either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI). 4. Have Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B disease not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment approach (see Section 12.8). 5. Have a Child-Pugh class A liver score within 7 days of first dose of study drug. 6. Have a predicted life expectancy of >3 months. 7. Have at least one measurable lesion based on RECIST 1.1 as confirmed by the blinded central imaging vendor. 8. Have a performance status of 0 or 1 using the ECOG Performance Scale within 7 days of first dose of study drug. 9. Have documented objective radiographic progression during or after treatment with sorafenib or intolerance to sorafenib. Sorafenib intolerance definition: Any Grade ≥2 drug-related AE which 1) despite supportive therapy, recurred after sorafenib treatment interruption of at least 7 days and dose reduction resulting in the subject requesting, or the physician recommending discontinuation due to toxicity. OR 2) required discontinuation of sorafenib due to toxicity, recommended by the physician with no rechallenge. 10. Subjects with chronic infection by HCV who are treated (successfully or treatment failure) or untreated are allowed on study. In addition, subjects with successful HCV treatment are allowed as long as there are ≥4 weeks between achieving sustained viral response (SVR12) and start of study drug. Successful HCV treatment definition: SVR12. 11. Has been treated with anti-Hepatitis B therapy. Controlled (treated) hepatitis B subjects will be allowed if they meet the following criteria: Antiviral therapy for HBV must be given for at least 12 weeks and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. Subjects on active HBV therapy with viral loads under 100 IU/ml should stay on the same therapy throughout study treatment. Subjects who are anti-HBc (+), negative for HBsAg, and negative or positive for anti-HBs, and who have an HBV viral load under 100 IU/mL do not require HBV anti-viral prophylaxis. 12. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication (Cycle 1, Day 1). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 13. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 – Contraception for the course of the study, starting with the first dose of study medication through at least 120 days or longer based on local regulation after the last dose of study medication. 14. Male subject of childbearing potential (Section 5.7.2) must agree to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, starting with the first dose of study medication (Cycle 1, Day 1) through 120 days after the last dose of study medication. 15. Demonstrate adequate organ function |
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E.4 | Principal exclusion criteria |
1. Is currently participating, or has participated, in a study of an investigational agent and received study therapy, herbal/complementary oral or IV medicine, or used an investigation device within 4 weeks of the first dose of treatment. Subjects must also have recovered from associated therapy (i.e., to Grade ≤1 or baseline) and from AEs due to any prior therapy. 2. Has received sorafenib within 14 days of first dose of study medication. 3. Has had esophageal or gastric variceal bleeding within the last 6 months. All subjects will be screened for esophageal varices, unless such screening has been performed in the past 12 months before first dose of treatment. If varices are present, they should be treated according to institutional standards before starting study treatment. 4. Has clinically apparent ascites on physical examination. 5. Portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac involvement of HCC based on imaging. 6. Has had clinically diagnosed hepatic encephalopathy in the last 6 months. Subjects on rifaximin or lactulose to control their hepatic encephalopathy are not allowed. 7. Had a solid organ or hematologic transplant. 8. Had prior systemic therapy for HCC in the advanced (incurable) setting other than sorafenib, prior to start study drug. 9. Has a known severe hypersensitivity (≥ Grade 3) to pembrolizumab, its active substance and/or any of its excipients. (Refer to the respective Investigator’s Brochure for a list of excipients.) 10. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 11. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor 12. Has received locoregional therapy to liver ranscatheter chemoembolization [TACE], transcatheter embolization [TAE], hepatic arterial infusion [HAI], radiation, radioembolization, or ablation) within 4 weeks prior to the first dose of study drug. Subject is not eligible if aforementioned treatments were administered between last dose of sorafenib and first dose of study medication. 13. Has had major surgery to liver or other site within 4 weeks prior to the first dose of study drug. 14. Has had a minor surgery (i.e., simple excision, tooth extraction) ≤7 days prior to the first dose of study treatment (Cycle 1, Day 1). 15. Has not recovered adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or complications from any intervention prior to starting therapy. 16. Has a diagnosed additional malignancy within 3 years prior to first dose of study with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cancers. 17. Has a known history of, or any evidence of, central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed by local site investigator. 18. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 19. Has an active infection requiring systemic therapy. 20. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator, including dialysis. 21. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial. 22. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the first dose of study medication through 120 days or longer based on local regulation after the last dose of trial treatment. 23. Has received prior immunotherapy including anti–PD-1, anti–PD-L1, or anti–PD-L2 agents, or if the subject has previously participated in Merck pembrolizumab clinical trials. 24. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 25. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry. 26. Has received a live vaccine within 30 days of planned start of study therapy (Cycle 1, Day 1). |
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E.5 End points |
E.5.1 | Primary end point(s) |
PFS per RECIST 1.1 criteria as assessed by the blinded central imaging vendor and OS will be used as the primary endpoints. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Two Interim analysis to be performed: IA1: expected approximately at month 22 at which time 183 OS events are expected to have been accumulated IA2: when approximately 232 OS events have been observed (expected at month 28 after study start)
Final efficacy analysis for OS (assuming not declared futile at the interim analysis); to be performed when at least 273 OS events have been observed, estimated to be 35 months after study start.
Results will be reviewed by an external data monitoring committee. |
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E.5.2 | Secondary end point(s) |
1. Compare ORR per RECIST 1.1 assessed by a blinded central imaging vendor. 2. Evaluate DOR, DCR and TTP per RECIST 1.1 assessed by a blinded central imaging vendor.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. ORR data locked at the time of the IA1, when approximately 183 OS events are observed, will be analyzed at IA1 if Type I error is available for the ORR analysis at this time point according to the multiplicity strategy; otherwise, these data will be analyzed at IA2 or FA, whenever the Type I error is available 2. Analyses of the DCR, TTP, and DOR data will be performed at the time of the interim and final analysis of OS. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Chile |
Colombia |
Hong Kong |
Israel |
Japan |
Korea, Republic of |
Mexico |
Philippines |
Puerto Rico |
Russian Federation |
Taiwan |
Thailand |
Turkey |
United States |
Belgium |
Denmark |
France |
Germany |
Hungary |
Ireland |
Italy |
Norway |
Poland |
United Kingdom |
Argentina |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |